Generally speaking, "polymers" are commonly understood to be any of a wide variety of synthetically produced, nonmetalic or organic compounds which can be molded into various forms and hardened for commercial use. They are made from high molecular weight macromolecules produce by "polymerizin" or chemically linking individual chemical sub-units or "monomers." There are essentially two types of polymers: homopolymers and copolymers. "Homopolymers" are made up of identical, repeating monomers chemically bonded together into polymer chains of various lengths. "Copolymers" are made from combinations of at least two different monomers which are polymerized to form chains of alternating different monomers or chains where the different monomers are randomly dispersed throughout.
There are both naturally occurring and synthetically produced polymers. Examples of natural polymers include, among others, proteins, polysaccharides, deoxyribose nucleic acid (DNA) and rubber, wherein the individual monomer sub-units are, respectively, amino acids, sugars, nucleic acids, and isoprene. Common synthetic polymers, which include plastics and silicones, are made from highly chemically reactive monomers including styrenes, acrylates, silanols and many others. Synthetic polymers have become one of the most important classes of molecules since their invention at the turn of the twentieth century. They have had a significant impact on every aspect of human life. However, significant efforts are continually underway to further our understanding of, and to advance the science of polymer chemistry. These efforts include the development of critically needed superior polymeric materials having presently unavailable combinations of physical and chemical properties.
The physical and chemical properties of both homopolymers and copolymers are dictated by the extent and the nature of polymer chain interactions within the polymers themselves. These interactions are, in turn, a function of the individual monomeric sub-units' sizes, weights, charges and chemical structures. The most important types of interactions between polymer chains are those chemical interactions which result in what is know in the art as "crosslinking." Crosslinking can be defined as a chemical process which joins individual polymer chains together by forming chemical bridges between and among the polymer chains. These "crosslinks" lock the polymer chains together into immense single molecules wherein the individual polymer chains can no longer slip over or relative to one another.
There are essentially two mechanisms by which polymers can be crosslinked. The first crosslinking method utilizes an external energy source, such as high energy radiation or heat, to induce interactions between chemically reactive functional groups within the individual monomers of each polymer chain forming new chemical bonds between the polymer chains. Polymers crosslinked using such an external energy source must be composed of monomers that are susceptible to such chemical reactions. Typically, such monomers have pendent, exposed chemical functional groups (portions of the monomer that are chemically reactive and extend away from the polymer chain, also referred to as "residues") which are capable of interacting with chemically compatible pendent groups on adjacent polymer chains. One example of this type of crosslinking involves the naturally occurring proteins found in animal skin. These proteins are complex polymers composed of numerous different monomers (amino acids) each containing highly reactive pendent chemical groups including sulfur, carboxylic acid and amine residues. As animals age, the cumulative effects of UV radiation (sun exposure) induce crosslinking between these protein molecules, changing the physical structure of these polymers and causing the skin to lose its natural elasticity and to become hard and wrinkled.
The second crosslinking mechanism utilizes the addition of exogenous crosslinking agents (an additional multifunctional molecule, not part of a polymer chain) in conjunction with the application of a chemical catalyst (or "accelerator") which promotes the reaction between the crosslinking agents and the chemical functional groups within the polymer chains. Such chemical reactions among polymer chains using crosslinking agents are not limited to polymers with pendent chemical groups. Rather, this form of chemical crosslinking works equally well with smaller monomer sub-units (such as "isoprene" or natural rubber) in which the only reactive functional group is a double chemical bond that is sequestered within the linear portion of the molecule (the straight part of the polymer chain, not extending from the macromolecule). Therefore, the use of crosslinking agents, either alone or in conjunction with external energy sources such as heat and radiation, provides an extremely versatile crosslinking mechanism which can produce profound changes in the polymer's properties.
One example of the dramatic changes that such exogenous crosslinking agents can produce in a polymer is the "vulcanization" of rubber. Vulcanization is the process of chemically bridging or linking the polymer's chains of natural rubber (polyisoprene) using elemental sulfur as the exogenous crosslinking agent. Heat and compounds such as peroxides, metallic oxides, and chlorinated quinones are also used to catalyze the chemical reactions between the polyisoprene chains and the sulfur. Without vulcanization, naturally occurring raw rubber is an extremely tacky, amorphous mass that will not hold a shape and is easily solubilized or dissolved by organic compounds such as gasoline, oil, and acetone. After crosslinking the raw rubber hardens and becomes less tacky, more resistant to cold induced hardening or heat induced softening, and resistant to organic solvents. This crosslinked rubber can be formed into commercial articles and products while hot and fluid, and will retain the formed shape upon cooling. Without crosslinking, natural rubber would not possess these beneficial properties required for its wide range of industrial applications including tires, shoes, electric insulators and waterproof articles.
These crosslinking techniques are commonly employed with both natural and synthetic polymers in order to create polymer compounds having optimized properties for particular applications. However, crosslinking polymers is a technically difficult process that must be precisely controlled for good results. Crosslinking agents can be simple inorganic compounds such as the sulfur used for vulcanization discussed above, or can be more complex organic compounds such as the divinyl benzene used in a wide variety of more exotic plastics. The amount of crosslinker added, the rate at which the crosslinking reaction is allowed to occur, and the density of the crosslinkable chemical functional groups present on the polymer chains all contribute to the resulting polymer's physical and chemical properties.
Consequently, the polymer chemist is faced with a series of difficult and conflicting choices that often result in compromises necessary to achieve the appropriate final compounds for a given application or purpose. Further, it is essential for the polymer chemist to understand the exact physical and chemical properties that are desired in the final polymer compounds before the crosslinking chemistry and mechanisms can be selected. Often, a process which accentuates one desirable physical property, such as polymer hardness, will have an adverse effect on another desirable property, such as surface tackiness or stickiness. Therefore, each crosslinking application requires a unique polymer formulation and an associated synthetic method for production including novel crosslinker and monomer combinations. Thus, it can be appreciated that the design and development of a polymer for a specific task is a daunting challenge that can involve completely new chemical and technological approaches.
Perhaps one of the most demanding applications for modern polymers is in the medical field, such as the field of ophthalmology which deals with the structure, function, repair of; and diseases of the eye. Where damage or disease (typically cataracts) requires the replacement of the eye's natural human lens, a polymer lens that has a unique combination of biological and physical properties is required. In addition to replacement intraocular lenses (IOLs), damaged corneas may require corneal implants or overlays. More recently, corrective medical implants known as "phakic" lenses have been proposed intended to augment or correct the light focusing function of the natural lens. Generally, the polymers used to produce such lenses and ocular implants must be optically clear, have a refractive index within the range suitable for human vision, and be biocompatible. Moreover, such implants must balance the competing physical properties of elasticity and flexibility with high strength and stability.
Early IOLs made from polymers such as polymethylmethacrylate (PMMA) were rigid and required a large incision (greater than 6 mm) in order to be inserted in the eye. This often resulted in a protracted and uncomfortable healing process which further stimulated the development of soft IOLs that could be folded and inserted through a considerably smaller opening (on the order of 4.0 mm or less) in order to reduce healing time and potential complications. However, folding an IOL for small incision implantation, though simple in theory, has been difficult to accomplish due to the strongly conflicting physical demands required of the polymers used to make such medical implants. Folding a lens for implantation significantly added to the demands placed on the polymer compounds used by requiring polymers that possess all of the previously mentioned attributes, optical clarity, non-tacky surfaces, stability and biocompatibility, among others, but by also requiring that the implant possess sufficient flexibility for folding while being sufficiently stable to resist damage and distortion induced by folding.
Initial attempts to find a polymeric compound that could be suitable for use with foldable IOLs centered around silicone monomers. Silicone polymer IOLs possessed excellent optical clarity, a suitable refractive index range, were generally biocompatible, and had excellent resilience. However, these lenses were relatively stiff and difficult to fold requiring larger than ideal incisions, special implantation tools and techniques, and have been known to unfold with nearly explosive intensity, potentially damaging delicate structures within the eye. Further, silicone implants have fallen out of favor due to latent biocompatibility concerns. As a result, a number of alternating, non-silicone organic polymers derived from acrylate and acrylate esters have been investigated and developed.
Many types of acrylate polymers have been used or proposed for foldable IOL fabrication. The majority of these proposed acrylate polymers are copolymer mixes of multiple monomers intended to produce the desired combination of properties possessed by each monomer component. However, the technical difficulties in making such soft, foldable optical polymers have been numerous, greatly slowing progress in the field. The ideal ocular implant or ocular lens, as previously stated, must be optically clear and must remain so for a prolonged period of time following implantation. The refractive index must be greater than 1.50 and the lens must be stably elastic and capable of stretching to 150% of its pre-stretch size before breaking (elongation factor). The implant must be soft enough to allow easy pre-insertion folding and it must have a non-tacky surface so that the inserted lens will unfold in a predictable manner without requiring further or difficult manipulation.
These often competing demands are extremely difficult to combine in a single material. For example, polymers with low tack surfaces are often too hard and crack when folded. Conversely, softer polymers which fold easily, are usually tacky, making them difficult to handle and complicating implantation and post insertion unfolding. Furthermore, the ideal ocular implant must have a stable elastic structure that will not be damaged, distorted, or destroyed by folding, while at the same time retaining all of the optical qualities required to function as a successful implant, lens, or corneal replacement. In spite of the almost continual advances in polymer chemistry and ocular implant design, the copolymers of the prior art have failed to yield IOLs and ocular implants having these ideal combinations of properties.
The majority of non-silicone polymers used for IOLs and ocular implants have been acrylate copolymers generally containing combinations of individual monomers in concentrations ranging from about 20 percent to 80 percent. These copolymers have been polymerized using a variety of techniques known in the art including external energy sources, exogenous crosslinkers, catalysts, and accelerators. Crosslinking, when performed, has generally been accomplished to stabilize the polymers utilizing low concentrations of low molecular weight diacrylates, multifunctional esters, epoxides and diols.
In contrast to these known chemical techniques and compositions, the present inventors, have surprisingly determined that by customizing the structural configurations of their crosslinking agents in accordance with the teachings of the present invention, they can produce homopolymer materials that possess markedly superior combinations of physical and chemical properties that were previously unobtainable in presently available homopolymers and copolymers. For example, lenses made from the homopolymers of the present invention, though optically clear and remarkably elastic, are physically stable and can be cast into very thin cross-sectional structures that were previously available only with significantly harder polymers.
As a result, ocular implants including IOLs can be produced having strongly tapered peripheral borders. This is particularly important with IOLs as the present invention now makes it possible to manufacture stably elastic intraocular lenses having sharp edges. As a result, cell migration between the back of the IOL and the posterior capsule of the eye [a process that often results in posterior capsule opacification (PCO) preventing light from reaching the retina of the eye and possibly leading to blindness] is believed to be significantly reduced. Prior art intraocular lenses cast from conventional acrylate polymers cannot be manufactured with such tapered circumferential borders having sharp edges due to the instability of conventional "soft" polymers when cast into such thin configurations. Consequently, patients with IOLs made from conventional polymers may be more susceptible to cell migration and resultant PCO.
Further, as known in the art, a common, non-invasive surgical procedure for eliminating posterior capsule opacity is to use a laser, such as an Yittrium Aluminum Garnet or YAG laser, to restore the patient's vision. This procedure, known as YAG Capsulotomy, produces an incision or hole in the opacified posterior capsule which then allows the passage of light through to the retina. However, a not uncommon complication of a laser capsulotomy is lens damage that can occur if a conventional acrylate polymer IOL is inadvertently struck by the YAG laser during the capsulotomy. This can cause damage ranging from pitting of the lens to complete fracturing of the lens necessitating its surgical removal and replacement.
In contrast, IOLs made from the homopolymers of the present invention, in addition to being less susceptible to PCO, are less susceptible to laser damage as well. In the rare event that PCO does occur in association with the lenses of the present invention, it is believed that the "rubbery" consistency of the homopolymers of the present invention will render IOLs made therefrom significantly less susceptible to the damaging effects of YAG lasers. Thus, pitting and cracking from misdirected lasers will be significantly reduced. Therefore, it is believed that stably soft, elastic IOLs manufactured from the new homopolymers of the present invention will significantly reduce the occurrence of PCO as well as reduce the occurrence of lens damage from laser capsulotomnies, if later required. This, in turn, will result in reduced patient discomfort and complications and in significantly reduced medical expenses.
A further advantage of the stable elastic homopolymers of the present invention is their remarkably high refractive indices. As a result, IOLs made from these homopolymers can be cast in even thinner cross-sectional shapes than were previously available without sacrificing their optical resolution. Thus, lenses produced in accordance with the teachings of the present invention can be folded into significantly smaller folded configurations, resulting in IOLs that can be inserted into the eye through smaller incisions (on the order of 3.2 to 4.0 mm) than IOLs made from known foldable polymers. Therefore, it should be appreciated by those skilled in the art that, just as the foldable silicone and acrylate polymers of the prior art represented a significant improvement over the hard, inflexible IOLs which preceded them, IOLs made from the homopolymers of the present invention provide yet another technological leap forward.
Accordingly, as will be discussed in detail herein, it is an object of the present invention to provide stably elastic, optically clear homopolymers crosslinked with rigid, structure enhancing crosslinkers.
It is another object of the present invention to provide soft, optically clear, foldable, high refractive index, IOLs that have low tack surfaces.
It is yet another object of the present invention to provide stably elastic IOLs having peripheral borders which taper to sharp edges that resists tearing or breaking.
It is another object of the present invention to provide IOLs made from "rubbery" homopolymers that are resistant to YAG laser damage.
It is still a further object of the present invention to provide stable elastic, foldable IOLs having sufficiently high refractive indices such that the IOLs can be sized to enable insertion through a truly small incision in the eye.